3-Aryl-3-hydroxy-2-methylenepropionic acid esters as fungicides

ABSTRACT

Compounds of formula I are described:  
                 
along with compositions thereof, methods of use thereof (particularly as fungicides), and methods of making the same.

RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional PatentApplication Serial No. 60/573,983, filed May 24, 2004, the disclosure ofwhich is incorporated by reference herein in its entirety.

FIELD OF THE INVENTION

The present invention concerns methylenepropionic acid esters,compositions thereof, and methods of use thereof for the control ofmicrobial pests, particularly fungal pests, on plants.

BACKGROUND OF THE INVENTION

The incidence of serious fungal infections, either systemic or topical,continues to increase for plants, animals, and humans. Many fungi arecommon in the environment and not harmful to plants or mammals. However,some fungi can produce disease in plants, humans and/or animals.

Fungicides are compounds, of natural or synthetic origin, which act toprotect plants against damage caused by fungi, including oomycetes.Current methods of agriculture rely heavily on the use of fungicides. Infact, some crops cannot be grown usefully without the use of fungicides.Using fungicides allows a grower to increase the yield of the crop andconsequently, increase the value of the crop. Numerous fungicidal agentshave been developed. However, the treatment of fungal infestations andinfections continues to be a major problem. Furthermore, fungicide andantifungal drug resistance has become a serious problem, rendering theseagents ineffective for some agricultural and therapeutic uses. As such,a need exists for the development of new fungicidal and antifungalcompounds (see, e.g., U.S. Pat. No. 6,673,827; See also U.S. Pat. No.6,617,330 to Walter, which describes pyrimidin-4-enamine as fungicides).

The antimalarial activity of 3-aryl-3-hydroxy-2-methylenepropionic acidshas been reported (M. K. Kundu et al. 1999, Bioorganic and MedicinalLetters 9, 731-6), but the reported esters are lower alkyl (e.g.,methyl) only.

SUMMARY OF THE INVENTION

The present invention relates to the field of fungicidal compositionsand methods. More particularly, the present invention concerns novelfungicidal methylenepriopionic acid esters and methods involvingapplication and use of fungicidally effective amounts of such compounds.The present invention also concerns methods useful in the preparation ofsuch methylenepriopionic acid esters.

The compounds and compositions of the present invention are useful ascrop protection agents to combat or prevent fungal infestations, or tocontrol other pests such as weeds, insects, or acarids that are harmfulto crops.

Accordingly, a first aspect of the present invention is a compound offormula I:

wherein:

R is selected from the group consisting of H, alkyl, alkoxyalkyl,haloalkyl, and aryl;

Ar is aryl, preferably not phenyl, and preferably heteroaryl;

Ar₁ is a 5 or 6-membered aromatic or heteroaromatic ring;

X₁, X₂, and X₃ taken individually from H, halogen, alkyl, alkenyl,alkynyl, haloalkyl, alkoxy, haloalkoxy, alkylthio, cyano, nitro; aryl oraryloxy or aryloxyalkyl, optionally substituted with halogen, alkyl,haloalkyl, alkoxy, alkylthio, haloalkoxy, cyano, nitro;

or X₁ and X₂ or X₂ and X₃ as an adjacent pair together form the group—Y—W-Z-, where: Y and Z are independently oxygen, sulphur, sulphonyl,carbonyl, or CR₁R₂; W is —(CR₃R₄)_(p)—(CR₅R₆)_(q)— or sulfonyl; R₁ andR₂ are independently hydrogen, halogen, or alkyl; R₃ and R₄ areindependently hydrogen, halogen, alkyl or haloalkyl or together form anoxo group; R₅ and R₆ are independently hydrogen, halogen, alkyl orhaloalkyl; p is 1 or 2; and q is 0 or 1;

R′ is C1-C4 alkylene optionally substituted with alkyl, haloalkyl,alkoxy, or cyano;

n is 0 or 1;

or a salt thereof such as an agriculturally or pharmaceuticallyacceptable salt thereof.

A second aspect of the present invention is a composition forcontrolling and preventing plant pathogenic microorganisms comprising,in combination, an active compound as described herein together with asuitable carrier.

A third aspect of the present invention is a method of controlling orpreventing infestation of cultivated plants by pathogenicmicroorganisms, comprising applying an active compound as describedherein to said plants, parts thereof or the locus thereof in an amounteffective to control said microorganisms.

A further aspect of the present invention is a method of controlling orpreventing infestation of technical materials by pathogenicmicroorganisms, comprising applying an active compound as describedherein to said technical materials, parts thereof or the locus thereofin an amount effective to control said microorganisms.

A further aspect of the present invention is a method of treating afungal infection in a subject in need thereof, comprising administeringan active compound as described herein to said subject in an amounteffective to treat said fungal infection.

A still further aspect of the present invention is the use of an activecompound as described herein for the preparation of a composition (e.g.,an agricultural formulation, a pharmaceutical formulation) for carryingout a method as described herein (e.g., an agricultural treatment asdescribed herein, the treatment of technical materials as describedherein, the treatment of a fungal infection in a subject as describedherein).

The foregoing and other objects and aspects of the present invention areexplained in greater detail below.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

“Alkyl” as used herein refers to a saturated hydrocarbon radical whichmay be straight-chain or branched-chain (for example, ethyl, isopropyl,t-amyl, or 2,5-dimethylhexyl) or cyclic (for example cyclobutyl,cyclopropyl or cyclopentyl) and contains from 1 to 24 carbon atoms. Thisdefinition applies both when the term is used alone and when it is usedas part of a compound term, such as “haloalkyl” and similar terms. Insome embodiments, preferred alkyl groups are those containing 1 to 4carbon atoms, which are also referred to as “lower alkyl.” In someembodiments preferred alkyl groups are those containing 5 or 6 to 24carbon atoms, which may also be referred to as “higher alkyl”.

“Alkenyl,” as used herein, refers to a straight or branched chainhydrocarbon containing from 2 to 24 carbons and containing at least onecarbon-carbon double bond formed by the removal of two hydrogens.Representative examples of “alkenyl” include, but are not limited to,ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl,5-hexenyl, 2-heptenyl, 2-methyl-1-heptenyl, 3-decenyl and the like.“Lower alkenyl” as used herein, is a subset of alkenyl and refers to astraight or branched chain hydrocarbon group containing from 1 to 4carbon atoms, and “higher alkenyl” has the corresponding meaning asdescribed above in connection with “higher alkyl”.

“Alkynyl,” as used herein, refers to a straight or branched chainhydrocarbon group containing from 2 to 24 carbon atoms and containing atleast one carbon-carbon triple bond. Representative examples of alkynylinclude, but are not limited, to acetylenyl, 1-propynyl, 2-propynyl,3-butynyl, 2-pentynyl, 1-butynyl and the like. “Lower alkynyl” as usedherein, is a subset of alkyl and refers to a straight or branched chainhydrocarbon group containing from 1 to 4 carbon atoms, and “higheralkynyl” has the corresponding meaning as described above in connectionwith “higher alkyl”.

“Alkoxy” refers to an alkyl radical as described above which also bearsan oxygen substituent which is capable of covalent attachment to anotherhydrocarbon radical (such as, for example, methoxy, ethoxy andt-butoxy).

“Alkylthio” as used herein refers to an alkyl group, as defined herein,appended to the parent molecular moiety through a thio moiety, asdefined herein. Representative examples of alkylthio include, but arenot limited, methylthio, ethylthio, tert-butylthio, hexylthio, and thelike.

“Aryl” or “aromatic ring moiety” refers to an aromatic substituent whichmay be a single ring or multiple rings which are fused together, linkedcovalently or linked to a common group such as an ethylene or methylenemoiety. The aromatic rings may each contain heteroatoms and hence “aryl”encompasses “heteroaryl” as used herein. Representative examples of arylinclude, azulenyl, indanyl, indenyl, naphthyl, phenyl,tetrahydronaphthyl, biphenyl, diphenylmethyl, 2,2-diphenyl-1-ethyl,thienyl, pyridyl and quinoxalyl. “Aryl” means substituted orunsubstituted aryl unless otherwise indicated and hence the arylmoieties may be optionally substituted with halogen atoms, or othergroups such as nitro, carboxyl, alkoxy, phenoxy and the like.Additionally, the aryl radicals may be attached to other moieties at anyposition on the aryl radical which would otherwise be occupied by ahydrogen atom (such as, for example, 2-pyridyl, 3-pyridyl and4-pyridyl).

“Heteroaryl” means a cyclic, aromatic hydrocarbon in which one or morecarbon atoms have been replaced with heteroatoms. If the heteroarylgroup contains more than one heteroatom, the heteroatoms may be the sameor different. Examples of heteroaryl groups include pyridyl,pyrimidinyl, imidazolyl, thienyl, furyl, pyrazinyl, pyrrolyl, pyranyl,isobenzofuranyl, chromenyl, xanthenyl, indolyl, isoindolyl, indolizinyl,triazolyl, pyridazinyl, indazolyl, purinyl, quinolizinyl, isoquinolyl,quinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, isothiazolyl, andbenzo[b]thienyl. Preferred heteroaryl groups are five and six memberedrings and contain from one to three heteroatoms independently selectedfrom O, N, and S. The heteroaryl group, including each heteroatom, canbe unsubstituted or substituted with from 1 to 4 substituents, aschemically feasible. For example, the heteroatom S may be substitutedwith one or two oxo groups, which may be shown as ═O.

“Agriculturally acceptable salt” means a salt the cation of which isknown and accepted in the art for the formation of salts foragricultural or horticultural use. Preferably the salts arewater-soluble.

“Cyano” as used herein refers to a —CN group.

“Halo” or “halogen,” as used herein, refers to —Cl, —Br, —I or —F.

“Haloalkyl,” as used herein, refers to at least one halogen, as definedherein, appended to the parent molecular moiety through an alkyl group,as defined herein. Representative examples of haloalkyl include, but arenot limited to, chloromethyl, 2-fluoroethyl, trifluoromethyl,pentafluoroethyl, 2-chloro-3-fluoropentyl, and the like.

“Hydroxy,” as used herein, refers to an —OH group.

“Nitro,” as used herein, refers to a —NO₂ group.

“Oxy,” as used herein, refers to a —O— moiety.

“Thio,” as used herein, refers to a —S— moiety.

The disclosures of all US patent references cited herein are to beincorporated herein in their entirety as if fully set forth.

2. Compounds. The compounds of this invention are represented by formulaI:

wherein:

R=H; alkyl; alkoxyalkyl; haloalkyl; aryl optionally substituted withhalogen, alkyl, alkynyl, haloalkyl, alkoxy, alkylthio, haloalkoxy,cyano, nitro; or heteroaryl optionally substituted with halogen, alkyl,alkynyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, cyano, nitro. Morepreferably, R is H; alkyl; aryl optionally substituted 1, 2, 3, or 4times with halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano; orheteroaryl (e.g., pyridyl, thienyl, benzthienyl, or furyl) optionallysubstituted 1, 2, 3, or 4 times with halogen, alkyl, haloalkyl, alkoxy,haloalkoxy, cyano. Most preferably, R is H; phenyl, or thienyloptionally substituted (e.g., substituted 1, 2, 3 or 4 times) withhalogen, alkyl, haloalkyl, alkoxy, or haloalkoxy.

Ar=aryl, preferably phenyl optionally substituted with halogen, alkyl,alkynyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, cyano, nitro;heteroaryl, especially 2-, 3- or 4-pyridyl optionally substituted (e.g.,substituted 1, 2, 3 or 4 times) with halogen, alkyl, alkynyl, haloalkyl,alkoxy, alkylthio, haloalkoxy, cyano, nitro; 2-thiazolyl, 5-thiazolyl,5-(1,2,3-thiadiazolyl), or 2-pyrimidinyl optionally substituted (e.g.,substituted 1, 2, 3 or 4 times) with halogen, alkyl, alkynyl, alkoxy,alkylthio, haloalkyl, cyano, nitro. More preferably, Ar=heteroaryl,especially 2- or 3-pyridyl, 2-thiazolyl, 5-thiazolyl, or5-(1,2,3-thiadiazolyl), unsubstituted or optionally substituted asdescribed above. Most preferably, Ar is 2- or 3-pyridyl or 2-thiazolyl,unsubstituted or optionally substituted as described above.

Ar₁=aryl, preferably a 5- or 6-membered aromatic ring comprised of 2-6C-atoms, 0-3 N-atoms, 0-1 O-atom, and 0-1 S-atom, especially phenyl,pyridyl, thienyl, and furyl. Preferably, Ar₁=phenyl or heteroaryl (e.g.,furyl, thienyl, or pyridyl). Most preferably, Ar₁ is phenyl, 2- or3-thienyl.

X₁, X₂, and X₃ taken individually from H, halogen, alkyl, alkenyl,alkynyl, haloalkyl, alkoxy, haloalkoxy, alkylthio, cyano, nitro; aryl oraryloxy or aryloxyalkyl, optionally substituted (e.g., substituted 1, 2,3 or 4 times) with halogen, alkyl, haloalkyl, alkoxy, alkylthio,haloalkoxy, cyano, or nitro,

or X₁ and X₂ or X₂ and X₃ as an adjacent pair together form the group—Y—W-Z-, where: Y and Z are independently oxygen, sulphur, sulphonyl,carbonyl, or CR₁R₂; W is —(CR₃R₄)_(p)—(CR₅R₆)_(q)— or sulfonyl; R₁ andR₂ are independently hydrogen, halogen, or alkyl; R₃ and R₄ areindependently hydrogen, halogen, alkyl or haloalkyl or together form anoxo group; R₅ and R₆ are independently hydrogen, halogen, alkyl orhaloalkyl; p is 1 or 2; and q is 0 or 1;

More preferably, X₁, X₂, and X₃ are each taken individually from H,halogen, alkyl, haloalkyl, alkoxy, haloalkoxy; aryl or aryloxy oraryloxyalkyl, optionally substituted (e.g., substituted 1, 2, 3 or 4times) with halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, or cyano.Most preferably, X₁, X₂, and X₃ are each taken individually from H,halogen, alkyl, haloalkyl, or aryloxy.

R′ is C1-C4 alkylene optionally substituted (e.g., substituted 1, 2, 3or 4 times) with alkyl, haloalkyl, alkoxy, or cyano. More preferably, R′is C1-C2 unsubstituted alkylene; and

n is 0 or 1.

Ar is preferably not phenyl, e.g., is preferably heteroaryl such as3-pyridyl (substituted or unsubstituted as described above). Ar₁ ispreferably phenyl (substituted or unsubstituted as described above) andis preferably not heteroaryl. Preferably at least one of X₁, X₂, and X₃is not H. In some embodiments R is preferably H; in other embodiments Ris preferably not H. In some embodiments n is preferably 0; in otherembodiments n is preferably not 0.

In one particular embodiment, compounds of the invention are subject tothe proviso that R is not H when Ar is 3-pyridyl, n is 0, Ar₁ is phenyl,and X₁, X₂, and X₃ are all H.

In another particular embodiment, compounds of the invention are subjectto the proviso that Ar is not 3-pyridyl when R is H, n is 0, Ar₁ isphenyl, and X₁, X₂, and X₃ are all H.

In still another particular embodiment, compounds of the invention aresubject to the proviso that Ar₁ is not phenyl when R is H, Ar is3-pyridyl, n is 0, and X₁, X₂, and X₃ are all H.

In still another particular embodiment, compounds of the invention aresubject to the proviso that at least one of X₁, X₂, and X₃ is not H whenR is H, Ar is 3-pyridyl, n is 0, Ar₁ is phenyl.

In some embodiments the Compound of Formula I is subject to the provisothat at least one compound, or all compounds, of Table 1 below areexcluded therefrom: TABLE 1 Compound Reference

1, 2

1, 2

1, 2

1, 2

1, 2

1, 2, 3

1, 2, 3

3

3

3

31. M Shi et al., 2002 Helvetica Chimica Acta, 85, 1051-7.2. M. Shi et al., 2003 Molecules, 7, 721-33.3. P. Perlmutteret al., 1996 Tetrahedron Lett., 37, 1715-8.

Methods of making. Compositions of generic structure I wherein R=H maybe prepared by the Morita-Baylis-Hillman reaction of acrylate ester IIwith aldehyde III:

The reaction is known and can be carried out in accordance with knowntechniques, or variations thereof that will be apparent to personsskilled in the art (See, e.g., D. Basavaiah et al., “The Baylis-HillmanReaction: A Novel Carbon-Carbon Bond Forming Reaction, Tetrahedron 52,8001-8062 (1996); see also U.S. Pat. No. 5,936,127). In general thereaction is carried out in the presence of a tertiary amine base such asDABCO (1,4-diazabicyclo[2.2.2]octane), trimethylamine, or DMAP(4-dimethylaminopyridine) with or without solvent or combinationsthereof such as water, 1,4-dioxane, tetrahydrofuran, formamide, alcohol.

Esters II are obtained from acylation of IV with acryloyl chloride V:

Acylation of IV with acryloyl chloride V is optimally conducted in aninert solvent such as dichloromethane in the presence of a tertiaryamine such as diisopropylethylamine at low temperature (−78° C.).

Compositions of generic structure I wherein R≠H may be prepared by oneof several methods. For compositions in which R=aryl or heteroaryl, theBaylis-Hillman product I may be reacted with an aryl halide, preferablyan aryl(heteroaryl) iodide (Ar₂I) or bromide (Ar₂Br) VI, in the presenceof a transition metal catalyst, preferably a palladium catalyst such aspalladium(II) diacetate, to produce I (R=Ar₂):

Such reactions are sometimes referred to as the Heck reaction, which maybe carried out in accordance with known techniques or variations thereofwhich will be apparent to those skilled in the art (see, e.g., U.S. Pat.Nos. 6,573,389; 6,489,258; and 5,162,532).Both the Z- and the E-isomers are generally obtained. Pure isomers areobtained after chromatographic (TLC or HPLC) separation. The preferredisomer is the Z-isomer:

Alternatively, compounds I in which R≠H may be prepared from an alkyneVII in a two-step reaction by first reduction with diisobutylaluminumhydride (DIBAL) followed by addition to an aryl aldehyde, ArCHO:

The preferred Z-isomer is produced stereoselectively in this reaction.

Exemplary compounds. Examples of compounds of the present inventioninclude, but are not limited to, the following: Compound NumberStructure Chemical Name 1

3-(Trifluoromethyl)phenylmethyl β-hydroxy-α-methylene-3-pyridinepropanoate; 2

3-(Trifluoromethyl)phenytmethyl β-hydroxy-α-methylene-2-thiazolepropanoate; 3

4-Chlorophenylmethyl β-hydroxy-α- methylene-2-thiazolepropanoate; 4

3,4-Dichlorophenylmethyl β-hydroxy-α- methylene-2-thiazolepropanoate; 5

3-(Trifluoromethyl)phenylmethyl Z-α-(α-hydroxy-3-pyridylmethyl)-3-phenylpropenoate; 6

4-Chloro-3-(trifluoromethyl)phenylmethyl Z-α-(α-hydroxy-3-pyridylmethyl)-3-phenylpropenoate; 7

3-(Trifluoromethyl)phenylmethyl Z-α-(α-hydroxy-3-pyridylmethyl)-3-(4-chloro)phenylpropenoate; 8

3-(Trifluoromethyl)phenylmethyl Z-α-(α-hydroxy-3-pyridylmethyl)-3-(3-thienyl)propenoate; 9

3-(Trifluoromethyl)phenylmethyl Z-α-(α-hydroxy- 3-pyridylmethyl)-3-(4-methoxy)phenylpropenoate; 10

1-(4-Chlorophenyl)-2-propyl β-hydroxy-α- methylene-2-thiazolepropanoate11

4-(Trifluoromethyl)phenylmethyl β-hydroxy-α-methylene-3-pyridinepropanoate 12

2-(Trifluoromethyl)phenylmethyl β-hydroxy-α-methylene-2-thiazolepropanoate 13

4-Chloro-3-(trifluoromethyl)phenylmethyl β-hydroxy-α-methylene-2-thiazolepropanoate 14

3-Chlorophenylmethyl β-hydroxy-α-methylene-2- thiazolepropanoate 15

3-(Trifluoromethyl)phenylmethyl β-hydroxy-α-methylene-2-oxazolepropanoate 16

3-(Trifluoromethyl)phenylmethyl β-hydroxy-α-methylene-5-thiazolepropanoate 17

3-(Trifluoromethyl)phenylmethyl β-hydroxy-α-methytene-5-(1,2,3-thiadiazole)propanoate 18

2,6-Dichlorophenylmethyl β-hydroxy-α- methylene-2-thiazolepropanoate 19

4-Chlorophenyl β-hydroxy-α-methylene-3- pyridinepropanoate 20

5-Chloro-2-thienylmethyl β-hydroxy-α- methylene-2-thiazolepropanoate 21

3-(Trifluoromethyl)phenylmethyl Z-α-(α-hydroxy-3-pyridylmethyl)-3-(2-chloro)phenylpropenoate 22

5-(3-Trifluoromethylphenyl)-2-furanmethyl β-hydroxy-α-methylene-3-pyridinepropanoate 23

4-(4-Chlorophenoxy)phenylmethyl β-hydroxy-α-methylene-3-pyridinepropanoate 24

4-(3-Chlorophenoxy)phenylmethyl β-hydroxy-α-methylene-3-pyridinepropanoate 25

3-(Trifluoromethyl)phenylmethyl Z-α-(α-hydroxy-3-pyridylmethyl)-3-(3-benzthienyl)propenoate 26

2,6-Dichlorophenylmethyl β-hydroxy-α- methylene-3-pyridinepropanoate 27

3,5-Dimethyl-4-methoxy-2-pyridinemethyl β-hydroxy-α-methylene-3-pyridinepropanoate 28

4-Phenoxyphenylmethyl β-hydroxy-α- methylene-3-pyridinepropanoate 29

5,6-Dichloro-3-pyridinemethyl β-hydroxy-α-methylene-2-thiazolepropanoate 30

4-Phenoxyphenylmethyl β-hydroxy-α- methylene-2-thiazolepropanoate 31

2-Chloro-3-(trifluoromethyl)phenylmethyl β-hydroxy-α-methylene-3-pyridinepropanoate 32

2-Chloro-3-(trifluoromethyl)phenylmethyl β-hydroxy-α-methylene-2-thiazolepropanoate 33

3-Chloro-4-methylphenylmethyl β-hydroxy-α-methylene-3-pyridinepropanoate 34

2-Fluoro-3-(trifluoromethyl)phenylmethyl β-hydroxy-α-methylene-3-pyridinepropanoate 35

3-Trifluoromethylphenyl β-hydroxy-α-methylene- 3-pyridinepropanoate 36

3-Chlorophenyl β-hydroxy-α-methylene-2- thiazolepropanoate 37

4-Chlorophenyl β-hydroxy-α-methylene-2- thiazolepropanoate 38

4-Phenoxyphenyl β-hydroxy-α-methylene-2- thiazolepropanoate 39

3-Chlorophenyl β-hydroxy-α-methylene-3- pyridinepropanoate 40

2-Chlorophenyl β-hydroxy-α-methylene-2- thiazolepropanoate 41

2,6-Dichlorophenyl β-hydroxy-α-methylene-2- thiazolepropanoate 42

2,3-Dichlorophenyl β-hydroxy-α-methylene-2- thiazolepropanoate 43

3,4-Dichlorophenyl β-hydroxy-α-methylene-2- thiazolepropanoate 44

3-Trifluoromethylphenyl β-hydroxy-α-methylene- 2-thiazolepropanoate 45

2,3-Dichlorophenyl β-hydroxy-α-methylene-3- pyridinepropanoate 46

2,4-Dichlorophenyl β-hydroxy-α-methylene-3- pyridinepropanoate 47

3,4-Dichlorophenyl β-hydroxy-α-methylene-3- pyridinepropanoate 48

3-Trifluoromethylphenyl β-hydroxy-α-methylene- 3-pyridinepropanoate 49

4-Methoxyphenyl β-hydroxy-α-methylene-3- pyradinepropanoate 50

3-(5-Chloro-2-pyridyloxy)phenylmethylβ-hydroxy-α-methylene-3-pyridinepropanoate 51

4-(5-Trifluoromethyl-2-pyridyloxy)phenylmethylβ-hydroxy-α-methylene-3-pyridinepropanoate 52

3-(5-Trifluoromethyl-2-pyridyloxy)phenylmethylβ-hydroxy-α-methylene-3-pyridinepropanoate 53

4-(2-Chloro-6-fluoro-4- trifluoromethylphenoxy)phenyl-methyl β-hydroxy-α-methylene-3-pyridinepropanoate 54

3-(2-Chloro-6-fluoro-4- trifluoromethylphenoxy)phenyl-methyl β-hydroxy-α-methylene-3-pyridinepropanoate 55

4-(5-Chloro-2-pyridyloxy)phenylmethylβ-hydroxy-α-methylene-3-pyridinepropanoate 56

4-(2,6-Dichloro-4-trifluoromethylphenoxy)phenyl- methylβ-hydroxy-α-methylene-3- pyridinepropanoate 57

3-(2,6-Dichloro-4-trifluoromethylphenoxy)phenyl- methylβ-hydroxy-α-methylene-3- pyridinepropanoate 58

3-(5-Chloro-2-pyridyloxy)phenylmethylβ-hydroxy-α-methylene-2-pyridinepropanoate 59

4-(5-Trifluoromethyl-2-pyridyloxy)phenylmethylβ-hydroxy-α-methylene-2-pyridinepropanoate 60

3-(5-Trifluoromethyl-2-pyndyloxy)phenylmethylβ-hydroxy-α-methylene-2-pyridinepropanoate 61

4-(2,6-Dichloro-4-trifluoromethylphenoxy)phenyl- methylβ-hydroxy-α-methylene-2- pyridinepropanoate 62

3-(2,6-Dichloro-4-trifluoromethylphenoxy)phenyl- methylβ-hydroxy-α-methylene-2- pyridinepropanoate 63

4-(2-Chloro-6-fluoro-4- trifluoromethylphenoxy)phenyl-methyl β-hydroxy-α-methylene-2-pyridinepropanoate 64

3-(2-Chloro-6-fluoro-4- trifluoromethylphenoxy)phenyl-methyl β-hydroxy-α-methylene-2-pyridinepropanoate 65

3-(5-Chloro-2-pyridyloxy)phenylmethylβ-hydroxy-α-methylene-2-thiazolepropanoate 66

4-(5-Trifluoromethyl-2-pyridyloxy)phenylmethylβ-hydroxy-α-methylene-2-thlazolepropanoate 67

3-(5-Trifluoromethyl-2-pyridyloxy)phenylmethylβ-hydroxy-α-methylene-2-thiazolepropanoate 68

4-(2,6-Dichloro-4-trifluoromethylphenoxy)phenyl- methylβ-hydroxy-α-methylene-2- thiazolepropanoate 69

3-(2,6-Dichloro-4-trifluoromethylphenoxy)phenyl- methylβ-hydroxy-α-methylene-2- thiazolepropanoate 70

4-(2-Chloro-6-fluoro-4- trifluoromethylphenoxy)phenyl-methyl β-hydroxy-α-methylene-2-thiazolepropanoate 71

3-(2-Chloro-6-fluoro-4- trifluoromethylphenoxy)phenyl-methyl β-hydroxy-α-methylene-2-thiazolepropanoate 72

4-Chloro-3,5-dimethylphenyl β-hydroxy-α- methylene-2-thiazolepropanoate73

4-Bromo-2,6-dimethylphenyl β-hydroxy-α- methylene-2-thiazolepropanoate74

Benzoylmethyl β-hydroxy-α-methylene-2- thiazolepropanoate 75

2-Acetylphenyl β-hydroxy-α-methylene-2- thiazolepropanoate 76

3-Acetylphenyl β-hydroxy-α-methylene-2- thiazolepropanoate 77

4-Benzoylphenyl β-hydroxy-α-methylene-2- thiazolepropanoate 78

3-Benzoylphenyl β-hydroxy-α-methylene-2- thiazolepropanoate 79

3-(Trifluoromethyl)phenylmethyl Z-α-(α-hydroxy-α-3-pyridylmethyl)-3-(3-chloro)phenylpropenaote 80

3-(Trifluoromethyl)phenylmethyl Z-α-(α-hydroxy-α-3-pyridylmethyl)-3-(3-fluoro)phenylpropenaote 81

3-(Trifluoromethyl)phenylmethyl Z-α-(α-hydroxy-α-3-pyridylmethyl)-3-(4-fluoro)phenylpropenaote 82

3-(Trifluoromethyl)phenylmethyl Z-α-(α-hydroxy-α-3-pyridylmethyl)-3-(2-fluoro)phenylpropenaote 83

3-(Trifluoromethyl)phenylmethyl Z-α-(α-hydroxy-α-3-pyridylmethyl)-3-(3,4- dichloro)phenylpropenaote 84

3-(Trifluoromethyl)phenylmethyl Z-α-(α-hydroxy-α-3-pyridylmethyl)-3-(3,4- difluoro)phenylpropenaote 85

3-(Trifluoromethyl)phenylmethyl Z-α-(α-hydroxy-α-3-pyridylmethyl)-3-(3,5- dichloro)phenylpropenaote 86

3-(Trifluoromethyl)phenylmethyl Z-α-(α-hydroxy-α-3-pyridylmethyl)-3-(3,5- difluoro)phenylpropenaote 87

3-(Trifluoromethyl)phenylmethyl Z-α-(α-hydroxy-α-3-pyridylmethyl)-3-(2,5- difluoro)phenylpropenaote 88

3-(Trifluoromethyl)phenylmethyl Z-α-(α-hydroxy-α-3-pyridylmethyl)-3-(2,5- dichloro)phenylpropenaote 89

3-(Trifluoromethyl)phenylmethyl Z-α-(α-hydroxy-α-3-pyridylmethyl)-3-(2-thienyl)propenaote 90

3-(Trifluoromethyl)phenylmethyl Z-α-(α-hydroxy-α-3-pyridylmethyl)-3-(5-chloro-2- thienyl)propenaote 91

3-(Trifluoromethyl)phenylmethyl Z-α-(α-hydroxy-α-3-pyridylmethyl)-3-(5-methyl-2- thienyl)propenaote 92

3-(Trifluoromethyl)phenylmethyl Z-α-(α-hydroxy-α-3-pyridylmethyl)-3-(3-methyl-2- thienyl)propenaote 93

3-(Trifluoromethyl)phenylmethyl Z-α-(α-hydroxy-α-3-pyridylmethyl)-3-(4-methyl-3- thienyl)propenaote 94

3-(Trifluoromethyl)phenylmethyl Z-α-(α-hydroxy-α-3-pyridylmethyl)-3-(2-chloro-3- thienyl)propenaote 95

3-(Trifluoromethyl)phenylmethyl Z-α-(α-hydroxy-α-3-pyridylmethyl)-3-(5-methyl-3- thienyl)propenaote 96

1-(3-Trifluoromethylphenyl)-1-propyl β-hydroxy-α-methylene-3-pyridinepropanoate 97

1-Phenyl-2-propyl β-hydroxy-α-methylene-3- pyridinepropanoate 98

1-(4-Chlorophenyl)ethyl β-hydroxy-α-methylene- 3-pyridinepropanoate 99

1-(2-Phenylphenyl)ethyl β-hydroxy-α-methylene- 3-pyridinepropanoate 100

1-(3-Thienyl)ethyl β-hydroxy-α-methylene-2- thiazolepropanoate 101

1-(4-Chlorophenyl)ethyl β-hydroxy-α-methylene- 2-thiazolepropanoate 102

1-(3-Trifluoromethylphenyl)-1-propyl β-hydroxy-α-methylene-3-pyridinepropanoate 103

1-(3-Trifluoromethylphenyl)-1-propyl β-hydroxy-α-methylene-2-thiazolepropanoate 104

1-(3-Trifluoromethylphenyl)ethyl β-hydroxy-α-methylene-3-pyridinepropanoate 105

3-(Methyl)phenylmethyl β-hydroxy-α-methylene- 2-thiazolepropanoate 106

3-(Trifluoromethoxy)-phenylmethyl β-hydroxy-α-methylene-3-pyridinepropanoate 107

3-(Trifluoromethoxy)-phenylmethyl β-hydroxy-α-methylene-2-thiazolepropanoate 108

4-(Trifluoromethoxy)-phenylmethyl β-hydroxy-α-methylene-3-pyridinepropanoate 109

4-(Trifluoromethoxy)-phenylmethyl β-hydroxy-α-methylene-2-thiazolepropanoate 110

4-(Trifluoromethyl)phenylmethyl β-hydroxy-α-methylene-2-thiazolepropanoate 111

3-(Trifluoromethyl)phenylethyl β-hydroxy-α-methylene-3-pyridinepropanoate 112

4-Chloro-3-(trifluoromethyl)phenylmethyl β-hydroxy-α-methylene-2-pyridinepropanoate 113

4-Chloro-3-(trifluoromethyl)phenylmethyl β-hydroxy-α-methylene-3-pyridinepropanoate 114

3,4-Dichlorophenylmethyl β-hydroxy-α- methylene-3-pyridinepropanoate 115

4-Chlorophenylethyl β-hydroxy-α-methylene-3- pyridinepropanoate 116

β-Chlorophenylethyl β-hydroxy-α-methylene-3- pyridinepropanoate 117

3-(Trifluoromethyl)phenylmethyl β-hydroxy-α-methylene-6-trifluoromethyl-3- pyridinepropanoate 118

2-Chlorophenylmethyl β-hydroxy-α-methylene-2- thiazolepropanoate 119

4-Chlorophenylethyl β-hydroxy-α-methylene-2- thiazolepropanoate 120

3-Chlorophenylethyl β-hydroxy-α-methylene-2- thiazolepropanoate 121

2-Chlorophenylethyl β-hydroxy-α-methylene-2- thiazolepropanoate 122

2,3,4,5,6-Pentafluorophenylmethyl β-hydroxy-α-methylene-2-thiazolepropanoate 123

2,3,4,5-Tetrafluorophenylmethyl β-hydroxy-α-methylene-2-thiazolepropanoate 124

3,5-(Bistrifluoromethyl)-phenylmethyl β-hydroxy-α-methylene-2-thiazolepropanoate 125

3-(Trifluoromethyl)phenylmethyl β-hydroxy-α-methylene-5-oxazolepropanoate 126

3-(Trifluoromethyl)phenylmethyl β-hydroxy-α-methylene-4-thiazolepropanoate 127

3,4-Difluorophenylmethyl β-hydroxy-α- methylene-2-thiazolepropanoate 128

3-Chloro-4-methylphenylmethyl β-hydroxy-α-methylene-2-thiazolepropanoate 129

3-Chloro-2-fluoro-5- (trifluoromethyl)phenylmethyl β-hydroxy-α-methylene-2-thiazolepropanoate 130

2-Fluoro-3-(trifluoromethyl)phenylmethyl β-hydroxy-α-methylene-2-thiazolepropanoate 131

2-Fluoro-5-(trifluoromethyl)phenylmethyl β-hydroxy-α-methylene-2-thiazolepropanoate 132

3-Fluoro-5-(trifluoromethyl)phenylmethyl β-hydroxy-α-methylene-2-thiazolepropanoate 133

4-Fluoro-3-(trifluoromethyl)phenylmethyl β-hydroxy-α-methylene-2-thiazolepropanoate 134

2-Chloro-5-(trifluoromethyl)phenylmethyl β-hydroxy-α-methylene-2-thiazolepropanoate 135

4-Methyl-3-(trifluoromethyl)phenylmethyl β-hydroxy-α-methylene-2-thiazolepropanoate 136

4-Methoxy-3-(trifluoromethyl)phenylmethyl β-hydroxy-α-methylene-2-thiazolepropanoate 137

3-(Trifluoromethyl)phenylmethyl β-hydroxy-α-methylene-2-chloro-3-pyridinepropanoate 138

2,6-Dichloro-4-pyridinemethyl β-hydroxy-α-methylene-2-thiazolepropanoate 139

2,5-Dichlorophenylmethyl β-hydroxy-α- methylene-2-thiazolepropanoate 140

3,5-Dichlorophenylmethyl β-hydroxy-α- methylene-2-thiazolepropanoate 141

2,3-Dichlorophenylmethyl β-hydroxy-α- methylene-2-thiazolepropanoate 142

5-Methylisoxazole-3-methyl β-hydroxy-α- methylene-2-thiazolepropanoate143

2-Thienylethyl β-hydroxy-α-methylene-3- pyridinepropanoate 144

3-Cyanophenylmethyl β-hydroxy-α-methylene-2- thiazolepropanoate 145

2-Chlorophenyl β-hydroxy-α-methylene-3- pyridinepropanoate 146

2,6-Dichlorophenyl β-hydroxy-α-methylene-3- pyridinepropanoate 147

4-Methylphenyl β-hydroxy-α-methylene-3- pyridinepropanoate 148

4-Methylphenyl β-hydroxy-α-methylene-2- thiazolepropanoate 149

2,4-Dichlorophenyl β-hydroxy-α-methylene-2- thiazolepropanoate 150

4-Methoxyphenyl β-hydroxy-α-methylene-2- thiazolepropanoate 151

4-Phenoxyphenyl β-hydroxy-α-methylene-2- thiazolepropanoate 152

4-Phenoxyphenyl β-hydroxy-α-methylene-3- pyridinepropanoate 153

3,4-Difluorophenyl β-hydroxy-α-methylene-3- pyridinepropanoate 154

3,4-Difluorophenyl β-hydroxy-α-methylene-2- thiazolepropanoate 155

2,4-Difluorophenyl β-hydroxy-α-methylene-3- pyridinepropanoate 156

2,4-Difluorophenyl β-hydroxy-α-methylene-2- thiazolepropanoate 157

4-Fluorophenyl β-hydroxy-α-methylene-3- pyridinepropanoate 158

4-Fluorophenyl β-hydroxy-α-methylene-2- thiazolepropanoate 159

4-Chloro-3-fluorophenyl β-hydroxy-α-methylene- 3-pyridinepropanoate 160

4-Chloro-3-fluorophenyl β-hydroxy-α-methylene- 2-thiazolepropanoate 161

4-Chloro-2-fluorophenyl β-hydroxy-α-methylene- 3-pyridinepropanoate 162

4-Chloro-2-fluorophenyl β-hydroxy-α-methylene- 2-thiazolepropanoate 163

2,6-Difluorophenyl β-hydroxy-α-methylene-3- pyridinepropanoate 164

2,6-Difluorophenyl β-hydroxy-α-methylene-2- thiazolepropanoate 165

2,5-Difluorophenyl β-hydroxy-α-methylene-3- pyridinepropanoate 166

2,5-Difluorophenyl β-hydroxy-α-methylene-2- thiazolepropanoate 167

2,3-Difluorophenyl β-hydroxy-α-methylene-3- pyridinepropanoate 168

2,3-Difluorophenyl β-hydroxy-α-methylene-2- thiazolepropanoate

Salts. The compounds described herein and, optionally, all their isomersmay be obtained in the form of their salts. Because some of thecompounds I have a basic center they can, for example, form acidaddition salts. Said acid addition salts are, for example, formed withmineral acids, typically sulfuric acid, a phosphoric acid or a hydrogenhalide, with organic carboxylic acids, typically acetic acid, oxalicacid, malonic acid, maleic acid, fumaric acid or phthalic acid, withhydroxycarboxylic acids, typically ascorbic acid, lactic acid, malicacid, tartaric acid or citric acid, or with benzoic acid, or withorganic sulfonic acids, typically methanesulfonic acid orp-toluenesulfonic acid. Together with at least one acidic group, thecompounds of formula I can also form salts with bases. Suitable saltswith bases are, for example, metal salts, typically alkali metal salts;or alkaline earth metal salts, e.g. sodium salts, potassium salts ormagnesium salts, or salts with ammonia or an organic amine, e.g.morpholine, piperidine, pyrrolidine, a mono-, di- or trialkylamine,typically ethylamine, diethylamine, triethylamine ordimethylpropylamine, or a mono-, di- or trihydroxyalkylamine, typicallymono-, di- or triethanolamine. Where appropriate, the formation ofcorresponding internal salts is also possible. Within the scope of thisinvention, agrochemical or pharmaceutically acceptable salts arepreferred.

3. Agrochemical compositions and use. Active compounds of the presentinvention can be used to prepare agrochemical compositions and used tocontrol fungi in like manner as other antifungal compounds. See, e.g.,U.S. Pat. No. 6,617,330; see also U.S. Pat. Nos. 6,616,952; 6,569,875;6,541,500, and 6,506,794.

Active compounds described herein can be used for protecting plantsagainst diseases that are caused by fungi. For the purposes herein,oomycetes shall be considered fungi. The active compounds can be used inthe agricultural sector and related fields as active ingredients forcontrolling plant pests. The active compounds can be used to inhibit ordestroy the pests that occur on plants or parts of plants (fruit,blossoms, leaves, stems, tubers, roots) of different crops of usefulplants, optionally while at the same time protecting also those parts ofthe plants that grow later e.g. from phytopathogenic micro-organisms.

Active compounds may be used as dressing agents for the treatment ofplant propagation material, in particular of seeds (fruit, tubers,grains) and plant cuttings (e.g. rice), for the protection againstfungal infections as well as against phytopathogenic fungi occurring inthe soil.

The active compounds may be used, for example, against thephytopathogenic fungi of the following classes: Fungi imperfecti (e.g.Botrytis, Pyricularia, Heiminthosporium, Fusarium, Septoria, Cercosporaand Alternaria) and Basidiomycetes (e.g. Rhizoctonia, Hemileia,Puccinia). Additionally, they may also be used against the Ascomycetesclasses (e.g. Venturia and Erysiphe, Podosphaera, Monilinia, Uncinula)and of the Oomycetes classes (e.g. Phytophthora, Pythium, Plasmopara).

Target crops to be protected with active compounds and compositions ofthe invention typically comprise the following species of plants: cereal(wheat, barley, rye, oat, rice, maize, sorghum and related species);beet (sugar beet and fodder beet); pomes, drupes and soft fruit (apples,pears, plums, peaches, almonds, cherries, strawberries, raspberries andblackberries); leguminous plants (beans, lentils, peas, soybeans); oilplants (rape, mustard, poppy, olives, sunflowers, coconut, castor oilplants, cocoa beans, groundnuts); cucumber plants (pumpkins, cucumbers,melons); fiber plants (cotton, flax, hemp, jute); citrus fruit (oranges,lemons, grapefruit, mandarins); vegetables (spinach, lettuce, asparagus,cabbages, carrots, onions, tomatoes, potatoes, paprika); lauraceae(avocado, cinnamon, camphor) or plants such as tobacco, nuts, coffee,eggplants, sugar cane, tea, pepper, vines including grape-bearing vines,hops, bananas, turf and natural rubber plants, as well as ornamentals(flowers, shrubs, broad-leafed trees and evergreens, such as conifers).This list does not represent any limitation.

The active compounds can be used in the form of compositions and can beapplied to the crop area or plant to be treated, simultaneously or insuccession with further compounds. These further compounds can be e.g.fertilizers or micronutrient donors or other preparations whichinfluence the growth of plants. They can also be selective herbicides aswell as insecticides, fungicides, bactericides, nematicides,molluscicides, plant growth regulators, plant activators or mixtures ofseveral of these preparations, if desired together with furthercarriers, surfactants or application promoting adjuvants customarilyemployed in the art of formulation.

The active compounds can be mixed with other fungicides, resulting insome cases in unexpected synergistic activities.

Mixing components which are particularly preferred are azoles such asazaconazole, bitertanol, propiconazole, difenoconazole, diniconazole,cyproconazole, epoxiconazole, fluquinconazole, flusilazole, flutriafol,hexaconazole, imazalil, imibenconazole, ipconazole, tebuconazole,tetraconazole, fenbuconazole, metconazole, myclobutanil, perfurazoate,penconazole, bromuconazole, pyrifenox, prochloraz, triadimefon,triadimenol, triflumizole or triticonazole; pyrimidinyl carbinoles suchas ancymidol, fenarimol or nuarimol; 2-amino-pyrimidine such asbupirimate, dimethirimol or ethirimol; morpholines such as dodemorph,fenpropidin, fenpropimorph, spiroxamin or tridemorph; anilinopyrimidinessuch as cyprodinil, pyrimethanil or mepanipyrim; pyrroles such asfenpiclonil or fludioxonil; phenylamides such as benalaxyl, furalaxyl,metalaxyl, R-metalaxyl, ofurace or oxadixyl; benzimidazoles such asbenomyl, carbendazim, debacarb, fuberidazole or thiabendazole;dicarboximides such as chlozolinate, dichlozoline, iprodine,myclozoline, procymidone or vinclozolin; carboxamides such as carboxin,fenfuram, flutolanil, mepronil, oxycarboxin or thifluzamide; guanidinessuch as guazatine, dodine or iminoctadine; strobilurines such asazoxystrobin, kresoxim-methyl, metominostrobin, SSF-129, methyl2[(2-trifluoromethyl)-pyrid-6-yloxymethyl]-3-methoxy-acrylate or2-[{.alpha.[(.alpha.-methyl-3-trifluoromethyl-benzyl)imino]-oxy}-o-tolyl]-glyoxylicacid-methylester-O-methyloxime (trifloxystrobin); dithiocarbamates suchas ferbam, mancozeb, maneb, metiram, propineb, thiram, zineb or ziram;N-halomethylthio-dicarboximides such as captafol, captan, dichlofluanid,fluoromide, folpet or tolyfluanid; copper compounds such as Bordeauxmixture, copper hydroxide, copper oxychloride, copper sulfate, cuprousoxide, mancopper or oxine-copper; nitrophenol derivatives such asdinocap or nitrothal-isopropyl; organo phosphorous derivatives such asedifenphos, iprobenphos, isoprothiolane, phosdiphen, pyrazophos ortoclofos-methyl; and other compounds of diverse structures such asacibenzolar-S-methyl, harpin, anilazine, blasticidin-S, chinomethionat,chloroneb, chlorothalonil, cymoxanil, dichione, diclomezine, dicloran,diethofencarb, dimethomorph, dithianon, etridiazole, famoxadone,fenamidone, fentin, ferimzone, fluazinam, flusulfamide, fenhexamid,fosetyl-aluminium, hymexazol, kasugamycin, methasulfocarb, pencycuron,phthalide, polyoxins, probenazole, propamocarb, pyroquilon, quinoxyfen,quintozene, sulfur, triazoxide, tricyclazole, triforine, validamycin,(S)-5-methyl-2-methylthio-5-phenyl-3-phenylamino-3,5-di-hydroimidazol-4-one(RPA 407213),3,5-dichloro-N-(3-chloro-1-ethyl-1-methyl-2-oxopropyl)-4-methylbenzamide(RH-7281), N-allyl-4,5-dimethyl-2-trimethylsilylthiophene-3-carboxamide(MON 65500),4-chloro-4-cyano-N,N-dimethyl-5-p-tolylimidazole-1-sulfon-amide(IKF-916),N-(1-cyano-1,2-dimethylpropyl)-2-(2,4-dichlorophenoxy)-propionamide (AC382042) or iprovalicarb (SZX 722).

Suitable carriers and adjuvants can be solid or liquid and aresubstances useful in formulation technology, e.g. natural or regeneratedmineral substances, solvents, dispersants, wetting agents, tackifiers,thickeners, binders or fertilizers.

A preferred method of applying an active compound of the invention, oran agrochemical composition which contains at least one of saidcompounds, is foliar application. The frequency of application and therate of application will depend on the risk of infestation by thecorresponding pathogen. However, the active compounds can also penetratethe plant through the roots via the soil (systemic action) by drenchingthe locus of the plant with a liquid formulation, or by applying thecompounds in solid form to the soil, e.g. in granular form (soilapplication). In crops of water such as rice, such granulates can beapplied to the flooded rice field. The active compounds may also beapplied to seeds (coating) by impregnating the seeds or tubers eitherwith a liquid formulation of the fungicide or coating them with a solidformulation.

The term locus as used herein is intended to embrace the fields on whichthe treated crop plants are growing, or where the seeds of cultivatedplants are sown, or the place where the seed will be placed into thesoil. The term seed is intended to embrace plant propagating materialsuch as cuttings, seedlings, seeds, and germinated or soaked seeds.

The active compounds are used in unmodified form or, preferably,together with the adjuvants conventionally employed in the art offormulation. To this end they are conveniently formulated in knownmanner to emulsifiable concentrates, coatable pastes, directly sprayableor dilutable solutions, dilute emulsions, wettable powders, solublepowders, dusts, granulates, and also encapsulations e.g. in polymericsubstances. As with the type of the compositions, the methods ofapplication, such as spraying, atomizing, dusting, scattering, coatingor pouring, are chosen in accordance with the intended objectives andthe prevailing circumstances.

Advantageous rates of application are normally from 5 g to 2 kg ofactive ingredient (a.i.) per hectare (ha), preferably from 10 g to 1 kga.i./ha, most preferably from 20 g to 600 g a.i./ha. When used as seeddrenching agent, convenient dosages are from 10 mg to 1 g of activesubstance per kg of seeds.

The formulation, i.e. the compositions containing the compound offormula I and, if desired, a solid or liquid adjuvant, are prepared inknown manner, typically by intimately mixing and/or grinding thecompound with extenders, e.g. solvents, solid carriers and, optionally,surface active compounds (surfactants).

Suitable carriers and adjuvants may be solid or liquid and correspond tothe substances ordinarily employed in formulation technology, such as,e.g. natural or regenerated mineral substances, solvents, dispersants,wetting agents, tackifiers, thickeners binding agents or fertilizers.Such carriers are for example described in WO 97/33890.

Further surfactants customarily employed in the art of formulation areknown to the expert or can be found in the relevant literature.

The agrochemical formulations will usually contain from 0.1 to 99% byweight, preferably from 0.1 to 95% by weight, of the compound of formulaI, 99.9 to 1% by weight, preferably 99.8 to 5% by weight, of a solid orliquid adjuvant, and from 0 to 25% by weight, preferably from 0.1 to 25%by weight, of a surfactant.

Whereas it is preferred to formulate commercial products asconcentrates, the end user will normally use dilute formulations.

The compositions may also contain further adjuvants such as stabilizers,antifoams, viscosity regulators, binders or tackifiers as well asfertilizers, micronutrient donors or other formulations for obtainingspecial effects.

4. Technical materials. The compounds and combinations of the presentinvention may also be used in the area of controlling fungal infection(particularly by mold and mildew) of technical materials, includingprotecting technical material against attack of fungi and reducing oreradicating fungal infection of technical materials after such infectionhas occurred. Technical materials include but are not limited to organicand inorganic materials wood, paper, leather, natural and syntheticfibers, composites thereof such as particle board, plywood, wall-boardand the like, woven and non-woven fabrics, construction surfaces andmaterials, cooling and heating system surfaces and materials,ventilation and air conditioning system surfaces and materials, and thelike. The compounds and combinations according the present invention canbe applied to such materials or surfaces in an amount effective toinhibit or prevent disadvantageous effects such as decay, discolorationor mold in like manner as described above. Structures and dwellingsconstructed using or incorporating technical materials in which suchcompounds or combinations have been applied are likewise protectedagainst attack by fungi.

5. Pharmaceutical uses. In addition to the foregoing, active compoundsof the present invention can be used in the treatment of fungalinfections of human and animal subjects (including but not limited tohorses, cattle, sheep, dogs, cats, etc.) for medical and veterinarypurposes. Examples of such infections include but are not limited toailments such as Onychomycosis, sporotichosis, hoof rot, jungle rot,pseudallecheria boydii, scopulariopsis or athletes foot, sometimesgenerally referred to as “white-line” disease, as well as fungalinfections in immunocomprised patients such as AIDS patients andtransplant patients. Thus, fungal infections may be of skin or ofkeratinaceous material such as hair, hooves, or nails, as well assystemic infections such as those caused by Candida spp., Cryptococcusneoformans, and Aspergillus spp., such as as in pulmonary aspergillosisand Pneumocystis carinii pneumonia. Active compounds as described hereinmay be combined with a pharmaceutically acceptable carrier andadministered or applied to such subjects or infections (e.g. topically,parenterally) in an amount effective to treat the infection inaccordance with known techniques, as (for example) described in U.S.Pat. Nos. 6,680,073; 6,673,842; 6,664,292; 6,613,738; 6,423,519;6,413,444; 6,403,063; and 60,42,845; the disclosures of which applicantsspecifically intend be incoroporated by reference herein in theirentirety.

“Pharmaceutically acceptable” is employed herein to refer to thosecompounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

“Pharmaceutically-acceptable carrier” as used herein means apharmaceutically-acceptable material, composition or vehicle, such as aliquid or solid filler, diluent, excipient, solvent or encapsulatingmaterial, involved in carrying or transporting the subjectpeptidomimetic agent from one organ, or portion of the body, to anotherorgan, or portion of the body. Each carrier must be “acceptable” in thesense of being compatible with the other ingredients of the formulationand not injurious to the patient. Some examples of materials which canserve as pharmaceutically-acceptable carriers include: (1) sugars, suchas lactose, glucose and sucrose; (2) starches, such as corn starch andpotato starch; (3) cellulose, and its derivatives, such as sodiumcarboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4)powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients,such as cocoa butter and suppository waxes; (9) oils, such as peanutoil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil andsoybean oil; (10) glycols, such as propylene glycol; (11) polyols, suchas glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters,such as ethyl oleate and ethyl laurate; (13) agar; (14) bufferingagents, such as magnesium hydroxide and aluminum hydroxide; (15) alginicacid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer'ssolution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21)other non-toxic compatible substances employed in pharmaceuticalformulations.

Formulations of the present invention include those suitable for oral,nasal, topical (including buccal and sublingual), rectal, vaginal and/orparenteral administration. The formulations may conveniently bepresented in unit dosage form and may be prepared by any methods wellknown in the art of pharmacy. The amount of active ingredient which canbe combined with a carrier material to produce a single dosage form willvary depending upon the host being treated, the particular mode ofadministration. The amount of active ingredient which can be combinedwith a carrier material to produce a single dosage form will generallybe that amount of the active ingredient which produces a therapeuticeffect. Generally, out of one hundred percent, this amount will rangefrom about 1 percent to about ninety-nine percent of active ingredient,preferably from about 5 percent to about 70 percent, most preferablyfrom about 10 percent to about 30 percent.

Methods of preparing these formulations or compositions include the stepof bringing into association a compound of the present invention withthe carrier and, optionally, one or more accessory ingredients. Ingeneral, the formulations are prepared by uniformly and intimatelybringing into association a peptide or peptidomimetic of the presentinvention with liquid carriers, or finely divided solid carriers, orboth, and then, if necessary, shaping the product.

The ointments, pastes, creams and gels may contain, in addition to theactive ingredient, excipients, such as animal and vegetable fats, oils,waxes, paraffins, starch, tragacanth, cellulose derivatives,polyethylene glycols, silicones, bentonites, silicic acid, talc and zincoxide, or mixtures thereof.

Powders and sprays can contain, in addition to a compound of thisinvention, excipients such as lactose, talc, silicic acid, aluminumhydroxide, calcium silicates and polyamide powder, or mixtures of thesesubstances. Sprays can additionally contain customary propellants, suchas chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons,such as butane and propane.

Formulations suitable for oral administration may be presented indiscrete units, such as capsules, cachets, lozenges, or tablets, eachcontaining a predetermined amount of the active compound; as a powder orgranules; as a solution or a suspension in an aqueous or non-aqueousliquid; or as an oil-in-water or water-in-oil emulsion. Suchformulations may be prepared by any suitable method of pharmacy whichincludes the step of bringing into association the active compound and asuitable carrier (which may contain one or more accessory ingredients asnoted above). In general, the formulations of the invention are preparedby uniformly and intimately admixing the active compound with a liquidor finely divided solid carrier, or both, and then, if necessary,shaping the resulting mixture. For example, a tablet may be prepared bycompressing or molding a powder or granules containing the activecompound, optionally with one or more accessory ingredients. Compressedtablets may be prepared by compressing, in a suitable machine, thecompound in a free-flowing form, such as a powder or granules optionallymixed with a binder, lubricant, inert diluent, and/or surfaceactive/dispersing agent(s). Molded tablets may be made by molding, in asuitable machine, the powdered compound moistened with an inert liquidbinder.

Pharmaceutical compositions of this invention suitable for parenteraladministration comprise one or more active compounds of the invention incombination with one or more pharmaceutically-acceptable sterileisotonic aqueous or nonaqueous solutions, dispersions, suspensions oremulsions, or sterile powders which may be reconstituted into sterileinjectable solutions or dispersions just prior to use, which may containantioxidants, buffers, bacteriostats, solutes which render theformulation isotonic with the blood of the intended recipient orsuspending or thickening agents.

Examples of suitable aqueous and nonaqueous carriers which may beemployed in the pharmaceutical compositions of the invention includewater, ethanol, polyols (such as glycerol, propylene glycol,polyethylene glycol, and the like), and suitable mixtures thereof,vegetable oils, such as olive oil, and injectable organic esters, suchas ethyl oleate. Proper fluidity can be maintained, for example, by theuse of coating materials, such as lecithin, by the maintenance of therequired particle size in the case of dispersions, and by the use ofsurfactants. These compositions may also contain adjuvants such aspreservatives, wetting agents, emulsifying agents and dispersing agents.Prevention of the action of microorganisms may be ensured by theinclusion of various antibacterial and other antifungal agents, forexample, paraben, chlorobutanol, phenol sorbic acid, and the like. Itmay also be desirable to include isotonic agents, such as sugars, sodiumchloride, and the like into the compositions. In addition, prolongedabsorption of the injectable pharmaceutical form may be brought about bythe inclusion of agents which delay absorption such as aluminummonostearate and gelatin.

When the compounds of the present invention are administered aspharmaceuticals, to humans and animals, they can be given per se or as apharmaceutical composition containing, for example, 0.1 to 99.5% (morepreferably, 0.5 to 90%) of active ingredient in combination with apharmaceutically acceptable carrier.

The preparations of the present invention may be given by any suitablemeans of administration including orally, parenterally, topically,transdermally, rectally, etc. They are of course given by forms suitablefor each administration route. For example, they are administered intablets or capsule form, by injection, inhalation, eye lotion, ointment,suppository, etc. administration by injection, infusion or inhalation;topical by lotion or ointment; and rectal by suppositories. Topical orparenteral administration is preferred.

“Parenteral administration” and “administered parenterally” as usedherein means modes of administration other than enteral and topicaladministration, usually by injection, and includes, without limitation,intravenous, intramuscular, intraarterial, intrathecal, intracapsular,intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal,subcutaneous, subcuticular, intraarticulare, subcapsular, subarachnoid,intraspinal and intrasternal injection and infusion.

Actual dosage levels of the active ingredients in the pharmaceuticalcompositions of this invention may be varied so as to obtain an amountof the active ingredient which is effective to achieve the desiredtherapeutic response, e.g., antimycotic activity, for a particularpatient, composition, and mode of administration, without being toxic tothe patient. The selected dosage level will depend upon a variety offactors including the activity of the particular active compoundemployed, the route of administration, the time of administration, therate of excretion of the particular active compound being employed, theduration of the treatment, other drugs, compounds and/or materials usedin combination with the particular inhibitor employed, the age, sex,weight, condition, general health and prior medical history of thepatient being treated, and like factors well known in the medical arts.A physician or veterinarian having ordinary skill in the art can readilydetermine and prescribe the effective amount of the pharmaceuticalcomposition required. For example, the physician or veterinarian couldstart doses of the compounds of the invention employed in thepharmaceutical composition at levels lower than that required in orderto achieve the desired therapeutic effect and gradually increase thedosage until the desired effect is achieved. As a general proposition, adosage from about 0.01 or 0.1 to about 50, 100 or 200 mg/kg will havetherapeutic efficacy, with all weights being calculated based upon theweight of the active compound, including the cases where a salt isemployed.

The present invention is explained in greater detail in the followingnon-limiting Examples.

EXAMPLE 1 3-(Trifluoromethyl)phenylmethylβ-hydroxy-α-methylene-3-pyridinepropanoate (Compound 1)

A mixture of 62 mg (0.27 mmol) of 3-(trifluoromethyl)phenylmethylacrylate, 29 mg (0.27 mmol) of pyridine-3-carboxaldehyde, and 30 mg(0.27 mmol) of 1,4-diazabicyclo [2.2.2]octane (DABCO) was thoroughlyshaken on a Vortex mixer, and then stored at 0° C. overnight. Theproduct was purified by preparative HPLC (prep HPLC) using a Gilson 210HPLC/fraction handler to give 47 mg (0.14 mmol; 52% yield) of thedesired Baylis-Hillman adduct, 3-(trifluoromethyl)phenylmethylβ-hydroxy-α-methylene-3-pyridinepropanoate. ¹H NMR (CDCl₃): δ 5.18 (s,2H), 5.63 (1H), 5.98 (1H), 6.45 (1H), 7.70 (d of t, 1H), 8.49 (d of d,1H), and 8.56 ppm (d, 1H). MS m/z: 338.1 (M+H).

EXAMPLES 2-43 Preparation of Additional Pyridinepropanoates

Compounds 11, 22-24, 26-28, 31, 33, 34, 50-57, 96-99, 102, 104, 106,108, 111, 113-116, and 143 above are prepared in essentially the samemanner as Compound 1 as described in Example 1 above. Compounds 58-64,and 112 are prepared in an analogous manner except thatpyridine-2-carboxaldehyde is employed in the Baylis-Hillman reaction.Compound 117 was also prepared in an analogous manner using6-trifluoromethylpyridine-3-carboxaldehyde, and compound 137 wasprepared using 2-chloropyridine-3-carboxaldehyde.

EXAMPLE 44 3,4-Dichlorophenylmethylβ-hydroxy-α-methylene-2-thiazolepropanoate (Compound 4)

A mixture of 59 mg (0.26 mmol) of 3,4-dichlorophenylmethyl acrylate, 27mg (0.24 mmol) of 2-thiazolecarboxaldehyde, and 31 mg (0.28 mmol) ofDABCO was thoroughly shaken on a Vortex mixer, and then stored at 0° C.overnight. The product was purified by prep HPLC to give 34 mg (0.10mmol; 42% yield) of the desired Baylis-Hillman adduct,3,4-dichlorophenylmethyl β-hydroxy-α-methylene-2-thiazolepropanoate. ¹HNMR (CDCl₃): δ 5.12 (2H), 5.76 (1H), 6.07 (1H), 6.49 (1H), 7.12 (d of d,1H), 7.71 ppm (d, 1H) MS m/z: 344.0 (M+H).

EXAMPLES 45-98 Preparation of Additional Thiazolepropanoates and RelatedHeterocyclylpropanoates

Compounds 2-3, 10, 12-14, 18, 20, 29, 30, 32, 65-71, 74, 100, 101, 103,105, 107, 109, 110, 118-124, 127-136, 138-142, and 144 are prepared inessentially the same manner as Compound 4 as described in Example 44above. The oxazolepropanoates 15 and 125 were prepared analogously byemploying 2-oxazolecarboxaldehyde and 5-oxazolecarboxaldehyde in theBaylis-Hillman reaction, respectively. The thiazolepropanoates 16 and126 were obtained using 5-thiazolecarboxaldehyde and4-thiazolecarboxaldehyde, respectively. Thiadiazolepropanoate 17 wasprepared by employing 1,2,3-thiadiazole-5-carboxaldehyde.

EXAMPLE 99 3-(Trifluoromethyl)phenylmethylZ-α-(α-hydroxy-3-pyridylmethyl)-3-phenylpropenoate (Compound 5)

A mixture of 100 mg (0.30 mmol) of 3-(trifluoromethyl)phenylmethylβ-hydroxy-α-methylene-3-pyridinepropanoate (Compound 1), 24 mg (0.11mmol) of palladium(II) acetate, 62 mg (0.58 mmol) of sodium carbonate,95 mg (0.29 mmol) of tetrabutylammonium bromide, and 62 μL (92 mg, 0.59mmol) of bromobenzene in 2 mL of anhydrous dimethylformamide (DMF) washeated at 100° C. overnight. The reaction mixture was then cooled,diluted with diethyl ether and filtered through magnesium sulfate(MgSO₄). The filtrate was washed with saturated sodium chloride anddried (MgSO₄). Solvent was removed by rotoevaporation. The crude productwas purified by preparative thin layer chromatography (prep TLC) to give14 mg (0.03 mmol) of 3-(trifluoromethyl)phenylmethylZ-α-(α-hydroxy-3-pyridylmethyl)-3-phenylpropenoate. ¹H NMR (CDCl₃): δ5.17 (d, 1H), 5.26 (d, 1H), 5.94 (d, 1H), 7.72 (1H), 8.50 (1H), and 8.58ppm (1H). MS m/z: 414.1 (M+H). The E-isomer, separated during prepTLCpurification, was also obtained (8 mg).

EXAMPLES 100-122 Preparation of Additional 3-Arylpropenoates

Compounds 6-9, 21, 25, and 79-95 are prepared in essentially the samemanner as compound 5 described in Example 99 above, by using theappropriately substituted bromo- or iodoaromatic in the Heck reaction.

EXAMPLE 123 4-Chlorophenyl β-hydroxy-α-methylene-3-pyridinepropanoate(Compound 19)

A mixture of 37 mg (0.20 mmol) of 4-chlorophenyl acrylate, 22 mg (0.22mmol) of pyridine-3-carboxaldehyde, and 22 mg (0.20 mmol) of DABCO wasthoroughly shaken on a Vortex mixer. After 1 hr at room temperature, themixture was diluted with dichloromethane. The DCM solution was washedwith dilute aqueous acetic acid, and the DCM removed by rotoevaporation.The residue was purified by preparative HPLC to give 10 mg (0.035 mmol,18% yield) of the desired Baylis-Hillman adduct, 4-chlorophenylβ-hydroxy-α-methylene-3-pyridinepropanoate. ¹H NMR (CDCl₃): δ 5.70 (1H),6.14 (1H), 6.64 (1H), 7.76 (d of t, 1H), 8.55 (d of d, 1H), and 8.64 ppm(d, 1H). MS m/z: 290.0 (M+H).

EXAMPLES 124-168 Preparation of Additional Phenyl Esters

Phenyl esters 35-49, 72, 73, 75-78, and 145-168 are prepared inessentially the same manner as compound 19 in Example 123 above.Generally, short reaction times (0.1-2 hr) were employed to maximizeyield of phenyl esters.

EXAMPLE 169 Biological Screening

Fungicidal activity for the compounds described in this invention wasdetermined using a microtiter plate format. In primary screening, testcompounds in 1 μL of dimethylsulfoxide (DMSO) are delivered toindividual wells of a 96-well microtiter plate. Then 100 μL of minimalmedia consisting of 1.5% agar is delivered to each well and allowed tocool. Finally, inoculation is carried out by the addition of 10 μL of anaqueous suspension of fungal spores to the surface of the solid agar.The plates are covered and incubated in a controlled environment at 20°C. Fungicidal activity is determined by visual inspection andphotometric analysis of fungal growth after 3-5 days, depending on thepathogen. Commercial standards (azoxystrobin, benomyl, captan,chlorothalonil, famoxadone, flusilazole, and propiconazole) are includedin all assays. Test pathogens include Septoria tritici, Stagonosporanodorum, Phytophthora infestans, and Botrytis cinerea. Dose responsedata for compounds found to be fungicidal in primary screening areobtained by screening 3-fold serial dilutions of the test compound.Fungicidal activity, noted as IC₅₀ values in μM concentration, forcertain of the compounds covered in this invention is included in thefollowing Table 2. The coefficient of variation (“C.V.”; ratio ofstandard deviation to the mean) expressed in percentage is given inparentheses. TABLE 2 IC₅₀ Values in μM Concentration and C.V. Values in% Compound Number B. cinerea P. infestans S. nodorum S. tritici 4 A B(d) C (b) B (b) 5 D D A (b) A (b) 19 D A (c) C (c) A (c) 24 D C C (c) A(d) 28 NT B (a) B A 30 C A (b) D BIC₅₀(μM): A = 0-5; B = 6-15; C = 16-25; D = +25C.V. (%): (a) = 0-5; (b) = 6-15; (c) = 16-25; (d) = +25NT = Not tested

The foregoing is illustrative of the present invention, and is not to beconstrued as limiting thereof. The invention is defined by the followingclaims, with equivalents of the claims to be included therein.

1. A compound of formula I:

wherein: R is selected from the group consisting of H, alkyl,alkoxyalkyl, haloalkyl, and aryl; Ar is heteroaryl; Ar₁ is a 5 or6-membered aromatic or heteroaromatic ring; X₁, X₂, and X₃ takenindividually from H, halogen, alkyl, alkenyl, alkynyl, haloalkyl,alkoxy, haloalkoxy, alkylthio, cyano, nitro; aryl or aryloxy oraryloxyalkyl, optionally substituted with halogen, alkyl, haloalkyl,alkoxy, alkylthio, haloalkoxy, cyano, nitro, or X₁ and X₂ or X₂ and X₃as an adjacent pair together form the group —Y—W-Z-, where: Y and Z areindependently oxygen, sulphur, sulphonyl, carbonyl, or CR₁R₂; W is—(CR₃R₄)_(p)—(CR₅R₆)_(q)— or sulfonyl; R₁ and R₂ are independentlyhydrogen, halogen, or alkyl; R₃ and R₄ are independently hydrogen,halogen, alkyl or haloalkyl or together form an oxo group; R₅ and R₆ areindependently hydrogen, halogen, alkyl or haloalkyl; p is 1 or 2; and qis 0 or 1; R′ is C1-C4 alkylene optionally substituted with alkyl,haloalkyl, alkoxy, or cyano; n is 0 or 1; or a salt thereof.
 2. Thecompound of claim 1, wherein R is H or alkyl.
 3. The compound of claim1, wherein R is aryl.
 4. The compound of claim 3, wherein R is phenyl orthienyl.
 5. The compound of claim 3, wherein said aryl is substitutedaryl.
 6. The compound of claim 1, wherein Ar is pyridyl optionallysubstituted with halogen, alkyl, alkynyl, haloalkyl, alkoxy, alkylthio,haloalkoxy, cyano or nitro.
 7. The compound of claim 6, wherein Ar is 2-or 3-pyridyl.
 8. The compound of claim 1, wherein Ar is thiazolyl orthiadiazolyl optionally substituted with halogen, alkyl, alkynyl,haloalkyl, alkoxy, alkylthio, haloalkoxy, cyano or nitro.
 9. Thecompound of claim 8, wherein Ar is 2-thiazolyl.
 10. The compound ofclaim 1, wherein Ar₁ is selected from the group consisting of phenyl,pyridyl, thienyl, and furyl.
 11. The compound of claim 1 selected fromthe group consisting of: Number Structure Chemical Name 1

3-(Trifluoromethyl)phenylmethyl β-hydroxy-α-methylene-3-pyridinepropanoate; 2

3-(Trifluoromethyl)phenylmethyl β-hydroxy-α-methylene-2-thiazolepropanoate; 3

4-Chlorophenylmethyl β-hydroxy-α- methylene-2-thiazolepropanoate; 4

3,4-Dichlorophenylmethyl β-hydroxy-α- methylene-2-thiazolepropanoate; 5

3-(Trifluoromethyl)phenylmethyl Z-α-(α-hydroxy-3-pyridylmethyl)-3-phenylpropenoate; 6

4-Chloro-3-(trifluoromethyl)phenylmethyl Z-α-(α-hydroxy-3-pyridylmethyl)-3-phenylpropenoate; 7

3-(Trifluoromethyl)phenylmethyl Z-α-(α-hydroxy-3-pyridylmethyl)-3-(4-chloro)phenylpropenoate; 8

3-(Trifluoromethyl)phenylmethyl Z-α-(α-hydroxy-3-pyridylmethyl)-3-(3-thienyl)propenoate; 9

3-(Trifluoromethyl)phenylmethyl Z-α-(α-hydroxy- 3-pyridylmethyl)-3-(4-methoxy)phenylpropenoate; 19

4-Chlorophenyl β-hydroxy-α-methylene-3- pyridinepropanoate 24

4-(3-Chlorophenoxy)phenylmethyl β-hydroxy-α-methylene-3-pyridinepropanoate 28

4-Phenoxyphenylmethyl β-hydroxy-α-methylene- 3-pyridinepropanoate 30

4-Phenoxyphenylmethyl β-hydroxy-α-methylene- 2-thiazolepropanoate 43

3,4-Dichlorophenyl β-hydroxy-α-methylene- 2-thiazolepropanoate

and salts thereof.
 12. A composition for controlling and preventingplant pathogenic microorganisms comprising, in combination, a compoundof claim 1 together with a suitable carrier.
 13. A method of controllingor preventing infestation of cultivated plants by pathogenicmicroorganisms, comprising: applying a compound according to claim 1 tosaid plants, parts thereof or the locus thereof in an amount effectiveto control said microorganisms.
 14. A method according to claim 13,wherein the microorganism is a fungal organism.
 15. The method of claim14, wherein said fungal organism is selected from the group consistingof Septoria tritici, Stagnospora nodorum, Phytophthora infestans, andBotrytis cinerea.
 16. A method of controlling or preventing infestationof a technical material by pathogenic microorganisms, comprising:applying a compound according to claim 1 to said technical material inan amount effective to control said microorganisms.
 17. A method oftreating a fungal infection in a subject in need thereof, comprising:administering a compound of claim 1 or a pharmaceutically acceptablesalt thereof to said subject in an amount effective to treat said fungalinfection.
 18. A method of making a compound of formula I:

wherein: R is H; Ar is heteroaryl; Ar₁ is a 5 or 6-membered aromatic orheteroaromatic ring; X₁, X₂, and X₃ taken individually from H, halogen,alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, alkylthio,cyano, nitro; aryl or aryloxy or aryloxyalkyl, optionally substitutedwith halogen, alkyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, cyano, ornitro, subject to the proviso that at least one of X₁, X₂, and X₃ is notH; or X₁ and X₂ or X₂ and X₃ as an adjacent pair together form the group—Y—W-Z-, where: Y and Z are independently oxygen, sulphur, sulphonyl,carbonyl, or CR₁R₂; W is —(CR₃R₄)_(p)—(CR₅R₆)_(q)— or sulfonyl; R₁ andR₂ are independently hydrogen, halogen, or alkyl; R₃ and R₄ areindependently hydrogen, halogen, alkyl or haloalkyl or together form anoxo group; R₅ and R₆ are independently hydrogen, halogen, alkyl orhaloalkyl; p is 1 or 2; and q is 0 or 1; R′ is C1-C4 alkylene optionallysubstituted with alkyl, haloalkyl, alkoxy, or cyano; and n is 0 or 1;comprising: reacting an acrylate ester of Formula II:

wherein X₁, X₂, X₃, Ar₁, and R′ are as given above with an aldehyde ofFormula III:

where Ar is as given above in a Morita-Baylis Hillman reaction in thepresence of a nucleophile to produce the compound of Formula I.
 19. Amethod of making a compound of formula I:

wherein: R is aryl or heteroaryl; Ar is heteroaryl; Ar₁ is a 5 or6-membered aromatic or heteroaromatic ring; X₁, X₂, and X₃ takenindividually from H, halogen, alkyl, alkenyl, alkynyl, haloalkyl,alkoxy, haloalkoxy, alkylthio, cyano, nitro; aryl or aryloxy oraryloxyalkyl, optionally substituted with halogen, alkyl, haloalkyl,alkoxy, alkylthio, haloalkoxy, cyano, or nitro, or X₁ and X₂ or X₂ andX₃ as an adjacent pair together form the group —Y—W-Z-, where: Y and Zare independently oxygen, sulphur, sulphonyl, carbonyl, or CR₁R₂; W is—(CR₃R₄)_(p)—(CR₅R₆)_(q)— or sulfonyl; R₁ and R₂ are independentlyhydrogen, halogen, or alkyl; R₃ and R₄ are independently hydrogen,halogen, alkyl or haloalkyl or together form an oxo group; R₅ and R₆ areindependently hydrogen, halogen, alkyl or haloalkyl; p is 1 or 2; and qis 0 or 1; R′ is C1-C4 alkylene optionally substituted with alkyl,haloalkyl, alkoxy, or cyano; n is 0 or 1; comprising: reacting acompound of formula I wherein R is H with an aryl halide of the formulaArZ, wherein Ar is aryl or heteroaryl and Z is halo, in the presence ofa transition metal catalyst to produce a compound of Formula I wherein Ris aryl or heteroaryl.
 20. A method of making a compound of formula I:

wherein: R is aryl or heteroaryl; Ar is heteroaryl; Ar₁ is a 5 or6-membered aromatic or heteroaromatic ring; X₁, X₂, and X₃ takenindividually from H, halogen, alkyl, alkenyl, alkynyl, haloalkyl,alkoxy, haloalkoxy, alkylthio, cyano, nitro; aryl or aryloxy oraryloxyalkyl, optionally substituted with halogen, alkyl, haloalkyl,alkoxy, alkylthio, haloalkoxy, cyano, nitro, or X₁ and X₂ or X₂ and X₃as an adjacent pair together form the group —Y—W-Z-, where: Y and Z areindependently oxygen, sulphur, sulphonyl, carbonyl, or CR₁R₂; W is—(CR₃R₄)_(p)—(CR₅R₆)_(q)— or sulfonyl; R₁ and R₂ are independentlyhydrogen, halogen, or alkyl; R₃ and R₄ are independently hydrogen,halogen, alkyl or haloalkyl or together form an oxo group; R₅ and R₆ areindependently hydrogen, halogen, alkyl or haloalkyl; p is 1 or 2; and qis 0 or 1; R′ is C1-C4 alkylene optionally substituted with alkyl,haloalkyl, alkoxy, or cyano; n is 0 or 1; comprising: reducing an alkyneof Formula VII:

with diisobutylaluminum hydride followed by addition of an aryl aldehydeof the formula ArCHO to produce a compound of Formula I.